Lung transplantation has become a viable option for the treatment of end-stage lung disease, as surgical techniques and immunosuppressive therapies have improved. The major cause of late mortality and morbidity post-transplant is obliterative bronchiolitis (0B), characterized by a progressive decline in lung function and small airway fibroobliteration. Recurrent acute rejection predisposes to 0B, but HLA mismatch, ischernic injury, and infection may contribute, resulting in irreversible injury to the airway epithelium. A mouse model of heterotopic airway transplantation reproduces the histopathological lesion of 0B, and has been employed to investigate the pathogenesis of this disorder. In this model, allograft epithelium regenerates and proliferates vigorously, yet undergoes rapid, irreversible injury, through augmented apoptotic pathways, leading to airway denudation and fibroobliteration. We hypothesize that the survival of the airway epithelium is critical to preventing the ingrowth of fibroproliferative matrix, and that pro-apoptotic mediators present in the alloirnmune environment alter the normal kinetics of airway epithelial cell cycle-regulated proliferation and repair. The overall objective of this proposal is to determine dominant pathways of airway epithelial death in OB as mediated through cell cycle regulators p2l and p53, and assess the role of TGFB-1, a potent inhibitor of airway epithelial cell growth, in modulating the expression of these proteins. Specifically, we will quantitatively assess epithelial cell proliferation and cell cycle regulatory proteins in heterotopic mouse airway grafts, test the role of TGFB-1 in promoting airway epithelial cell death using in-vitro cell culture and in-vivo animal models, and lastly evaluate the kinetics of airway epithelial cell growth and death in clinical specimens with active OB lesions. This project will involve intensive training in tissue culture of rodent and human airway epithelium, protein chemistry, immunology, molecular biology techniques, and pulmonary pathophysiology and pathology, in a unique environment that will facilitate the development of independent investigation in pulmonary diseases.